The project consists of a series of clinical trials using the oral surgery model to evaluate novel agents, methods of administration and drug combinations in comparison to standard analgesic therapy. Previous studies demonstrated the superiority of an investigational analgesic, flurbiprofen, in comparison to acetaminophen and oxycodone plus acetaminophen, and that etidocaine, a long-acting local anesthetic, suppresses postoperative pain. A factorial study demonstrated that the combination of flurbiprofen and etidocaine results in independent and additive effects to markedly suppress pain in comparison to standard therapy while resulting in fewer side effects. A current investigation is evaluating the ability of proglumide, an antagonist of cholecystokinin, to potentiate morphine analgesia in the oral surgery model. Interim data analysis suggests that 5.0 mg of proglumide plus 4.0 mg of morphine sulfate results in analgesia comparable to 8.0 mg of morphine sulfate. The analgesic specificity of drugs acting at opiate receptor subtypes is being evaluated in a clinical trial of spiradoline, a structurally unique kappa receptor agonist. The interaction of proglumide and spiradoline with endogenous pain inhibitory substances such as plasma beta-endorphin is also being evaluated in these latter studies. These investigations may contribute to the development of novel opioid analgesics with enhanced efficacy but without the liabilities of traditional opioids such as morphine.